Bleeding disorders andperiodontology

PH I L I P VA S S I L O P O U L O S & KE N T PA L C A N I S

Delivery of patient care encompasses a wide range

and variety of challenges, one of which is unexpected

clinical bleeding. Clinical bleeding can be presented

in two forms: the first can occur during surgery; and

the second can manifest several days after the pro-

cedure. In both situations, the clinician will need to

take immediate action to control the hemorrhage and

stabilize the patient. The present article will review

bleeding disorders and their management. The dis-

cussion will address the following issues:

• significance of bleeding disorders in the treatment

of periodontal disease.

• prevalence of bleeding disorders.

• basic physiology of hemostasis.

• classification and definition.

• medical diagnosis.

• management of periodontal patients with bleeding

disorders.

• current concepts and new approaches in treating

periodontal patients with bleeding disorders.

Significance of bleeding disordersin the treatment of periodontaldisease

The extent and severity of periodontal disease

determines the necessity for a surgical or nonsurgical

treatment approach in its management. Both of the

above share the common goal of debriding the root

surfaces. Periodontal cases can be more complicated

and treatment may involve tooth extractions and

dental implant surgical procedures in order to restore

loss of function (14, 52).

Patients undergoing periodontal treatment may be

at increased risk for bleeding. Although the incidence

of bleeding disorders is low in the general population,

a hemorrhagic episode during or after periodontal

procedures can lead to detrimental complications

and can place the patient’s life at risk (60).

An increasing number of medically compromised

patients within the aging population manifest signs of

periodontal disease. Illnesses, along with pharmaco-

therapy, may contribute to the tendency for excessive

bleeding. Polypharmacia and medical conditions

found in an aging population are the main reasons to

reconsider treatment approaches in patients with

bleeding disorders and periodontal disease (19).

The dental professional must be aware of the

possibility that periodontal patients with no previous

indication of bleeding can manifest their first bleed-

ing event in the dental office. A detailed knowledge of

intra-operative and postoperative hemostatic meas-

ures under challenging hemorrhagic situations is

considered a priority for the dental care professional.

If a patient has been diagnosed with a hematologic

deficiency, the dental care provider needs to consult

the patient’s hematologist. Thus, the dental care

provider can modify the treatment to be provided

and may refer the patient out to a multidisciplinary

comprehensive care center for further care and

investigation (29).

Prevalence of bleeding disorders

Coagulation factor abnormalities are the most com-

mon inherited bleeding disorders. However, the

overall frequency rate of congenital coagulation dis-

orders in the general population is low, at 10–20 per

100,000 individuals (50).

Von Willebrand disease, Hemophilia A and He-

mophilia B account for 95–97% of all coagulation

deficiencies (40, 42).

Von Willebrand disease is the most frequently

inherited bleeding disorder, affecting 0.8–2% of the

general population in Europe and America. However,

von Willebrand disease often remains undiagnosed

and, as a result, statistical prevalence does not indi-

cate the actual prevalence of the disease (55, 68, 69).

211

Periodontology 2000, Vol. 44, 2007, 211–223

Printed in Singapore. All rights reserved

� 2007 The Authors.

Journal compilation � 2007 Blackwell Munksgaard

PERIODONTOLOGY 2000

For example, how many people within dental care

settings who experience bleeding are actually tested

for von Willebrand disease?

Hemophilia A is the most common of the inherited

coagulopathies, with a prevalence of up to one per

5,000 male births (70). Hemophilia B occurs in one

per 50,000 male births. In the U.S.A., 18,000 people

are diagnosed with hemophilia (61). How many of

these people have experienced bleeding during den-

tal treatment? Further studies in this area would shed

more light on the risks of bleeding and periodontal

treatment.

Other coagulation factor deficiencies, such as fac-

tor I (fibrinogen), factor II (prothrombin), factor VII

(proconvertin), factor X (Stuart-Prower) and factor XI

(plasma thromboplastin antecedent), are even more

rare (1, 41, 48–50). Literature regarding such defici-

encies and periodontal treatment is not substantial.

Currently, more than one million people receive

anticoagulation therapy each year in the U.S.A. (38).

Furthermore, ca. 200,000 people have chronic renal

failure, which affects clotting (46). Because of the

presence of inherited and acquired bleeding disor-

ders in a population that increasingly undergoes

periodontal therapy, it is important to review the

basics of hemostasis in order to understand the nat-

ure of bleeding disorders in greater detail.

Basic physiology of hemostasis

Hemostasis can be viewed as either primary or sec-

ondary (27), or as a four-phase process (58). Primary

hemostasis entails platelet plug formation and lasts

for 2–3 seconds (27). It is considered to be the pre-

dominant mechanism of blood loss stoppage in

capillaries and small-diameter vessels (27).

Secondary hemostasis is associated with fibrin

synthesis and its deposition, which surrounds and

links the platelet aggregate and provides stabilization

of the hemostatic clot (27). Localized formation of the

fibrin clot in the injury site restores the blood flow of

arteries and veins (27). This stage can take up to

several minutes to complete (27). Having briefly

outlined primary and secondary hemostasis, we will

now address the hemostatic process, which consists

of four phases: vascular; platelet; coagulation; and

fibrinolytic (58) (Fig. 1).

Vascular phase

Tha vascular phase starts immediately after the dis-

ruption of blood vessels. Vascular smooth muscle

cells become readily activated and contract to reduce

the vascular lumen and thus maintain vascular

integrity (58). As a result, the endothelial cells be-

come closely situated and this inhibits blood loss

(58). Also, blood concentrated in the extravascular

space exerts pressure, which further contributes to

diminished blood loss (58).

Platelet phase

Platelets have an anucleated discoid shape, 2–4 lm in

diameter. They are derived from megakaryocytes in

the bone marrow. Under normal circumstances, they

number 150,000–400,000/ll and circulate in the

periphery of the vascular lumen (53). The platelet

phase is characterized by platelet adhesion, acti-

vation, secretion and aggregation (53).

HEMOSTASIS

Vascular1. Smooth cells contraction2. Extravascular pressure

Platelet1. Adhesion2. Activation3. Secretion4. Aggregation

CoagulationPathways1. Tissue factor – dependent2. Intrinsic

Fibrinolytic1. Lysis of fibrin network into peptides2. Fibrinogen deactivation

Fig. 1. Hemostasis phases.

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Vassilopoulos & Palcanis

The platelets adhere to the exposed subendothelial

connective tissue through glycoprotein receptors lo-

cated in the platelet membrane (27). Glycoprotein

receptors GP Ib-IX-V and GP Ia-IIa, as well as GP VI,

play a predominant role in the binding of platelets at

the site of injury (27). Von Willebrand factor acts as a

bridge between GP Ib-IX-V and underlying collagen

(27) (Fig. 2) and, as a result, initiates platelet activa-

tion. With this �bridging�, the platelet is able to move

towards the direction of blood flow until it binds

firmly to the vascular wall through the GP Ia-IIa and

GP VI receptors.

The activation of platelets leads to the formation of

filopodia and, at this time, the platelet cell is pre-

pared for secretion. The first wave of platelet aggre-

gation ends before platelet granule secretion (58), the

next step in the platelet phase.

The second wave begins with the granule release

(58). Platelets contain a number of storage granules,

including alpha granules and dense granules, as well

as glycogen particles, mitochondria and lysosomes

(53). Both categories of granules play an important

role in hemostasis. Moreover, the second wave of

platelet aggregation is associated with hemostatic

plug organization through the binding of GP IIb–IIIa

platelet adhesive receptor with fibrinogen (58)

(Fig. 2).

Coagulation phase

The third phase of hemostasis, known as coagulation,

includes a complex series of protelytic reactions that

occur on the phospholipid membrane of the activa-

ted platelets (58). During coagulation, a variety of

factors, including enzymes, cofactors and contact

factors, contribute to thrombin formation and the

important conversion of fibrinogen to fibrin (35).

The traditional way of division of the coagulation

system into extrinsic and intrinsic pathways has been

underscored, and the new model of coagulation is

viewed as two inter-related pathways merging into

the common pathway, which entails the formation

PlateletPlatelet

Vascular endothelium

Collagen

vWF Platelet

GP IIb-IIIa GP IIb-IIIa GP IIb-IIIa GP IIb-IIIa

Platelet

GP VI

vWF

GP Ib-IX

vWF

Fig. 2. Platelet adhesion and aggregation. GP, glycoprotein; vWF, von Willebrand factor.

213

Bleeding disorders and periodontology

of prothrombinase complex (8). The tissue factor-

dependent pathway, also known as the extrinsic

pathway, acts rapidly and produces a small quantity

of thrombin, triggering the initiation of the intrinsic

pathway that is responsible for the main production

of thrombin through the prothrombinase complex (7,

58). The prothrombinase complex is composed of

activated factor X, activated factor V, phospholipid

membrane and calcium ions (58) (Fig. 3).

In the extrinsic (or tissue factor-dependent) path-

way, factor VII is activated from the tissue factor and

provokes the activation of factor X and formation of

the prothrombinase complex. The tissue factor

pathway inhibitor regulates the extrinsic pathway,

inhibiting the factor VII–tissue factor complex (58)

(Fig. 3).

In the intrinsic pathway, the contact factors pre-

kallikrein and high-molecular-weight kininogen and

factor XII form a complex that activates factor IX and

XI, resulting in the formation of prothrombinase

complex (27) (Fig. 3).

Thrombin is associated with acceleration of the

clotting process through the activation of factors V, VII,

VIII, XI and XIII, as well as through platelet aggrega-

tion, in addition to its role in fibrin formation (Fig. 4).

The platelet clot is transformed to the fibrin clot

under the influence of the activated fibrin stabiliza-

tion factor XIII, which crosslinks the fibrin monomers

(27) (Fig. 3).

In addition, thrombin stimulates the thrombin-

activatable fibrinolysis inhibitor to protect the fibrin

clot from premature dissolution (8).

Prothrombinase complexXa/VaCa++

Phospholipid

XII XIIa

XI XIa

IX IXa

X Xa

Intrinsic pathway

PrekallikreinHigh-molecular-weight kininogen

Tissue-factor pathway

VIIa-tissuefactor

complex

Prothrombin Thrombin

TFPI

Fibrinogen Fibrin monomer Fibrin

XIII

XIIIa

Fig. 3. Coagulation phase. TAFI, thrombin-activatable fibrinolysis inhibitor.

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Vassilopoulos & Palcanis

Fibrinolytic phase

Fibrinolysis is the last stage of hemostasis and initi-

ates disintegration of the hemostatic plug and the

tissue repair process. Two plasminogen activators –

tissue plasminogen activator and urinary plasmino-

gen activator – have the task of transforming

plasminogen to plasmin, which breaks down the fi-

brin network to fibrin peptides and, to a lesser extent,

deactivates fibrinogen (58). The fibrinolytic action is

limited at the site of the hemostatic clot and is

regulated by specific plasminogen activator inhibi-

tors and by a-2-antiplasmin that acts directly on

plasmin (8) (Fig. 5).

Classification and definition

Bleeding disorders are hematological conditions

characterized by a functional impairment in the

hemostatic process.

The bleeding disorders are classified in two broad

categories: inherited or hereditary; and acquired.

We will highlight the most common hematologic

disorders in relation to each of the hemostatic

phases.

Inherited bleeding disorders

Vascular disorders

Hereditary vascular defects are associated with syn-

dromes and are characterized by blood vessel devel-

opmental abnormalities. Hereditary hemorrhagic

telangiectacia, or Osler–Weber–Rendu syndrome and

Ehlers–Danlos syndrome, are classic examples that

manifest bleeding diathesis because of malformed

blood vessels and defects in the subendothelial and

perivascular connective tissue respectively (27, 58).

Platelet disorders

Platelet disorders are classified into quantitative and

qualitative disorders. An example of a quantitative

disorder is congenital thrombocytopenia, which is

characterized by a low number of platelets, specific-

ally if the platelet count is <150,000/ll (30).

THROMBIN

COAGULATION Activation

V, VII, VIII, XI, XIII

FIBRIN FORMATION

PLATELET AGGREGATION

FIBRIN CLOT PROTECTION

TAFI

Fig. 4. Thrombin functions. TAFI, thrombin-activatable fibrinolysis inhibitor.

Plasmin

Fibrin clot Fibrin peptides

Plasminogen

Urinary plasminogenacivator

Tissue plasminogenactivator

α-2 -antiplasmin

Fig. 5. Fibrinolytic phase.

215

Bleeding disorders and periodontology

On the other hand, qualitative platelet disorders

are divided into platelet receptor and platelet secre-

tion defects (8). The platelet receptor defects include

a number of syndromes, such as Bernard–Soulier

syndrome and Glanzmann’s thrombasthenia (53, 54).

Platelet secretion defects, known as storage pool de-

fects, can be caused by absent or deficient granules.

These disorders are the most common of the con-

genital platelet disorders, which include Gray platelet

syndrome, dense granule deficiency and Wiscott–

Aldrich syndrome (8, 53).

Coagulation disorders

Von Willebrand disease is described as a qualitative

or quantitative deficiency of von Willebrand factor,

leading to a hematologic disorder (28). The von

Willebrand factor is composed of a series of plasma

protein multimers originally presented in the form of

a propeptide in the endothelial and megakaryocyte

cells (68). The von Willebrand factor acts as a con-

necting link between the injured subendothelial col-

lagen and the platelet receptor GP Ib, providing an

aggregate of platelets at the bleeding site (39). The

subsequent binding reinforcement provided by the

large multimers enhances the formation of fibrin and

the conversion to a stable hemostatic clot. von

Willebrand factor binds, in a complimentary manner,

to coagulation factor VIII and makes it more resistant

to the degradation process (16).

Sadler (56) classified von Willebrand disease into

three types. Types I and III are associated with partial

and total deficiency of von Willebrand factor,

respectively. Type II represents a qualitative disorder.

All the forms are inherited in an autosomal-dominant

manner, except for subtype IIN, which has an auto-

somal-recessive pattern (20).

Hemophilia A is defined as a recessive X chromo-

some-linked coagulation factor VIII disorder (9).

Carrier mothers transmit the hemophilia gene to

sons. Hemophilia A, known also as classic hemo-

philia, accounts for 80–85% of all hemophilia and is

grouped into three types, according to the level and

activity of coagulation factor VIII (14). In the severe

form, coagulation factor activity is <1%, compared

with the normal and moderate ranges (1–5%) and the

mild range (5–49%) (15).

Hemophilia B, or Christmas disease, is 10 times

less frequent than hemophilia A and is inherited in

the same manner (15). The deficiency in factor IX

may have different pathogenic mechanisms, charac-

terized by inefficient activation, insufficient binding

and decreased half life of factor IX (15). Other coa-

gulopathies have been reported in the literature, with

very low incidence rates (8, 41, 50).

Fibrinolytic disorders

There have been few cases published in which a

plasminogen activator deficiency has been detected,

as well as a-2-antiplasmin deficiency, leading to

hemorrhagic episodes (8). The limited number

of specialized laboratory centers, and the inability of

current tests to identify these abnormalities, have

contributed to the underdiagnosis of congenital

fibrinolytic disorders (8).

Acquired bleeding disorders

Vascular disorders

Acquired vascular defects are associated with diseases

affecting the epithelium and connective tissue of blood

vessels. Scurvy (as a vitamin C deficiency) affects the

formation of connective tissue and thus the perivas-

cular connective tissue network. The weakened capil-

laries are prone to hemorrhage and create a series of

challenging bleeding episodes (27, 58).

Platelet disorders

Acquired platelet disorders can be categorized as

quantitative and qualitative disorders (30).

A number of conditions lead to acquired thrombo-

cytopenia, including decreased platelet produc-

tion, increased platelet destruction, and increased

sequestration. The disease entities associated with

decreased platelet production involve primarily ane-

mia, leukemia and medication-induced infection. In

regard to platelet destruction, the cause can be

immunologic or nonimmunologic in nature, such

as immune thrombocytopenic and nonimmune

thrombocytopenic purpura. Moreover, hypersplen-

ism, as a secondary feature of portal hypertension

and splenic neoplastic conditions, can remove a large

portion of platelets from plasma (30).

Furthermore, acquired qualitative platelet disor-

ders are present in chronic renal failure. A defect in

platelet receptor glycoprotein IIb–IIIa, and the asso-

ciated hyperviscosity of this disease, contribute to the

impairment of platelet function (38).

Coagulation disorders

Patients with hepatic failure as a result of hepatitis B

and C, cirrhosis or alcohol abuse, present decreased

synthesis of coagulation factors (38, 47).

Patients on long-term anticoagulation therapy

develop acquired coagulopathies (37). The orally

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Vassilopoulos & Palcanis

administered anticoagulant, coumarin (36, 59), intra-

venously administered unfractionated heparin (36,

59), and subcutaneously administered low-molecular-

weight heparin (33), are commonly used medications

that inhibit the coagulation system and are of partic-

ular importance to periodontal patients. Specifically,

coumarin interferes with the vitamin K-dependent

factors II, VII, IX, and X. Meanwhile, fractionated and

unfractionated heparin enhances the action of anti-

thrombin III, resulting in the deactivation of activated

prothrombin and activated factors IX, X, XI, and plas-

min. Moreover, and to a lesser degree, it inhibits the

transformation of fibrinogen to fibrin (33).

Patients taking aspirin or aspirin-containing com-

pounds are candidates for excessive bleeding. Aspirin

affects the transition of arachidonic acid to throm-

boxane A by blocking the enzyme cyclooxygenase.

The enzymatic inhibition is irreversible and interferes

with the homeostatic ability of existing circulating

platelets. The duration of its effect is equal to the life

span of platelets: c. 7–10 days (17, 36, 59).

Other antiplatelet medications, administered as a

part of anticoagulation therapy, are ADP receptor

inhibitors and fibrinogen receptor (GP IIb–IIIa)

inhibitors. ADP receptor inhibitors, such as clopi-

dogrel bisulfate and ticlodipine hydrochloride, and

GP IIb–IIIa inhibitors, such as tirofiban, abciximab

and eptifibatide, result in the irreversible inhibition

of platelet aggregation (17, 36, 59). Dipyridamole

inhibits reversibly the phosphodiesterase enzyme,

which reduces cAMP. cAMP inhibits platelet activa-

tion and aggregation. The duration of the antiplatelet

effect is estimated to be up to 24 hours.

Nonsteroidal anti-inflammatory medications act

reversibly on the cyclooxygenase enzyme, which

interferes with platelet hemostatic function. Hemo-

static dysfunction is limited to the presence of the

medication in the circulation (59). Patients with

malabsorption syndromes placed on long-term anti-

biotic therapy, and others lacking vitamin K, may

manifest coagulation disorders because of synthetic

impairment of vitamin K-dependent factors (38).

Fibrinolytic disorders

Liver disease can reduce the metabolization of cer-

tain fibrinolytic activators, thus impacting the

fibrinolytic stage and subsequently dissolution of the

hemostatic plug. On the other hand, certain medi-

cations, such as streptokinase, administered to des-

troy the formed clot in thromboembolic disorders,

create the potential for fibrinolysis. Prostate carci-

noma cases are also associated with increased plas-

min levels and fibrinolysis (43, 47).

Medical diagnosis and bleeding

Medical diagnosis of a patient with a bleeding dis-

order is based on the medical history, physical

examination and laboratory evaluation. Taking a

patient’s medical history is of paramount import-

ance in determining the nature of hemorrhagic

disease, whether inherited or acquired. Physical

examination, revealing multiple and small-in-size

mucocutaneous hemorrhagic lesions in the form of

petechiae and ecchymoses, is indicative of vascular

or platelet disorders. Moreover, superficial cuts, with

persistent and often profuse bleeding, may indicate

the presence of a vascular or a platelet bleeding

disorder (53).

The characteristics of severe inherited coagulation

bleeding disorders include enlarged, solitary, or deep

dissecting hematomas, as well as haemarthrosis,

intramuscular and intracranial hemorrhage (53).

Laboratory evaluation contributes adjunctively in

establishing the diagnosis. Screening tests for bleed-

ing disorders include partial thromboplastin time,

prothrombin time and platelet count. Partial throm-

boplastin time evaluates the intrinsic and common

pathways, with normal values ranging from 25 to

35 seconds, depending on the laboratory, and always

require a control sample. Prothrombin time evaluates

the extrinsic and common pathways, and averages

between 11 and 15 seconds, based on the laboratory.

Running a control sample is mandatory. The platelet

count depicts the number of platelets in the circula-

tion, with the normal range being 150,000–400,000/

ll. Other specialized tests can be performed by the

hematologist to identify specific defects causing the

bleeding disorder (47, 57).

Management of periodontalpatients with bleeding disorders

Pre-operative precautions

Pre-operative management of patients starts with a

medical history focusing on the previous bleeding

history of the patient and medical conditions asso-

ciated with bleeding.

A detailed medical history must include the fol-

lowing.

• Previous hemorrhagic episodes after trauma or

surgery, or even spontaneous bleeding.

• Family history regarding hereditary bleeding dis-

orders.

217

Bleeding disorders and periodontology

• Current illnesses, such as hepatic and renal failure,

and a list of medications interfering with hemos-

tasis, such as nonsteroidal anti-inflammatory

drugs and antibiotics.

• Anticoagulation medications, such as coumarin,

heparin, aspirin, clopidogrel, and ticlodipine.

Patients with a family history of bleeding or past

hemorrhagic episodes should be encouraged to seek

medical advice to find the cause of bleeding. Con-

sultation with the primary care physician and a

hematologist is deemed necessary, and proper rec-

ommendations will be proposed by the medical

health providers concerning the dental management

of these patients. The nature and severity of an ac-

quired bleeding disorder, and the degree of invasive

dental procedures, determine the need for treatment

to be provided in a specialized treatment center set-

ting. In such cases, the hematologist will suggest the

proper pharmacological regimen to be administered

prophylactically in order to achieve hemostasis (43).

Patients presenting with certain illnesses, such as

hepatic failure or renal failure, or those taking anti-

coagulant medications, aspirin, antiplatelet medica-

tions and/or nonsteroidal anti-inflammatory drugs,

are prone to bleeding during delivery of dental

treatment. The treatment protocol may have to be

modified to minimize the risk of intra-operative and

postoperative bleeding. First, patients diagnosed with

chronic renal failure should be managed the day after

dialysis when heparin has been cleared from the

system and the patient regains his/her strength after

the dialysis process (71). Second, patients lacking

vitamin K, because of malabsorption syndrome,

should receive vitamin K supplement before the

dental appointment to restore liver function and the

synthesis of coagulation factors. If the patient has

liver failure, the dental management of the patient

should involve platelet transfusion in a hospital set-

ting (38). Third, the management of patients on

anticoagulant therapy has been controversial. Anti-

coagulant treatment is indicated in the following

medical conditions: deep-vein thrombosis, pul-

monary embolism, atrial fibrillation, mechanical

prosthetic heart valve, valvular heart disease, cere-

brovascular accident, transient ischemic attacks, and

myocardial infarction (4, 36, 37). Anticoagulant

medications reduce the risk of embolism and in-

crease the probability of bleeding during and after

the dental procedure. There is considerable evidence

supporting the safety of dental procedures performed

on anticoagulated patients (31). There are a number

of case reports concerning serious thromboem-

bolic events developing after the interruption of

anticoagulation treatment (65, 67). In some in-

stances, the likelihood of a thromboembolic episode

in patients who discontinued taking the anticoagu-

lant medications is three times higher than that of a

bleeding event in patients who remained on the

anticoagulant regimen (66). Detailed risk assessment

has to be performed on each patient, and the possi-

bility of life-threatening situations has to be taken

into serious consideration before the dental practi-

tioner suggests discontinuation of anticoagulation

therapy. Pre-operative care of patients on antico-

agulant therapy with coumarin involves the con-

tinuation, reduction or withdrawal of the medication

(10, 31, 36, 59). The decision should be based on the

international normalized ratio value, the invasiveness

and extent of dental procedure, current illnesses and

medications (59). The international normalized ratio

is a key component in the dental treatment of these

patients. When the international normalized ratio is

£3.5, periodontal surgical procedures can be carried

out on these patients in a dental office (36, 37, 59).

When the international normalized ratio is >3.5, the

anticoagulation regimen has to be adjusted. The

dental care provider should consult with the medical

care provider and describe, in detail, the periodontal

procedure and risk for bleeding (66, 67). The dental

professional may decide if modification of the anti-

coagulant regimen will place the patient at risk for a

thromboembolic event (65). A safe approach entails

reduction of the coumarin dose 2–3 days before the

procedure and repetition of international normalized

ratio testing the morning of the procedure to ensure

that the value is <4 (36, 37, 59). The international

normalized ratio can also be measured at home using

a portable device (36, 43, 59). International normal-

ized ratio therapeutic levels for most medical condi-

tions range between 2.5 and 3.5 (4). International

normalized ratio values may be increased because of

the use of medications enhancing the effect of cou-

marin, a diet rich in vitamin K and/or compliance

reasons (59). International normalized ratio values

can be normalized to 3.5 by making minor adjust-

ments involving the reduction, but not the discon-

tinuation, of coumarin. Entire withdrawal of cou-

marin is not recommended because of the rebound

thrombotic effect noticed especially in patients with

prosthetic cardiac valves when coumarin intake re-

initiated (59, 65, 66). It takes up to 4 days for the

international normalized ratio values to return to

normal (59). Therefore, reducing the international

normalized ratio value may increase the risk for

thrombosis in patients with other concomitant ill-

nesses such as liver and renal disease, and patients

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Vassilopoulos & Palcanis

with increased alcohol consumption (59). Extensive

and invasive periodontal surgical procedures in such

patients should be performed in a hospital setting,

and intravenous unfractionated heparin should be

given as a substitute for coumarin (59). Unfraction-

ated heparin can be interrupted 4–6 hours before the

surgical procedure, thus substantially minimizing the

time the patient is under a suboptimal level of anti-

coagulation and subsequently reducing the risk for a

thromboembolic event (31). Anticoagulation treat-

ment is resumed 12–18 hours after the dental pro-

cedure (31). Fractionated or low-molecular-weight

heparin may provide an alternative substitute for

coumarin, without the need for the patient to be

admitted to hospital (33, 36). Subcutaneous

administration of low-molecular-weight heparin

provides the benefit of conveniently adjusting the

anticoagulation regimen at the point of care (33, 36).

Patients taking aspirin should discontinue the

medication at least 3 days, and up to 7 days, before

the surgical procedure (17, 36, 37, 59). However,

consultation with the physician is mandatory. In re-

gard to other anti-platelet medications, such as ADP

inhibitors and GP IIb–IIIa inhibitors, discontinuation

of the medication 7 days before the procedure gives

adequate time for the level of circulating functional

platelets to be restored (17, 59). Patients taking other

antiplatelet medications, such as dipyridamole or

nonsteroidal anti-inflammatory drugs, and present-

ing a bleeding potential, should consult their physi-

cian. The physician should recommend the proper

regimen according to the half life of the administered

medication. In most cases, three half lives of this

medication provide sufficient time for the medication

to be removed from the circulation (17, 59).

In addition, the care of patients with bleeding

disorders must be placed into new perspective. Pre-

ventive dental care for patients with known bleeding

disorders has to be intensive and should include

regular dental visits, frequent professional tooth

cleanings, oral hygiene reinforcement, fluoride sup-

plements and mouthrinses, a low-sugar diet and

annual radiographic examination. Continued efforts

to prevent dental diseases, and arresting dental dis-

eases at the initial stage, eliminate the need for

invasive dental procedures and reduce the risk of

associated prolonged bleeding (7).

Patients with diagnosed congenital bleeding dis-

orders should consult their hematologist before any

treatment is rendered. Dental management protocols

proposed for these patients are individualized and

based on a very specific design plan by the dental

care professional and the hematologist. Key compo-

nents taken into consideration are the severity of the

bleeding disorder and the type of dental procedure

and associated potential for bleeding. To minimize

the risk to the patient, a dental care professional must

be familiar with the pathology of inherited bleeding

disorders, and recommended dental procedures to be

performed on a high-risk patient should be carried

out in a facility in which all necessary equipment and

biological products are available (7, 32).

Intra-operative actions

Intra-operative measures include a number of sys-

temic and local measures administered prior to, or

during, the procedure to prevent unlikely bleeding

diathesis. Patients with inherited bleeding disorders

require specific systemic hematologic coverage in

order for the dental professional to provide the

necessary dental care (23, 24). Every case is unique,

and the severity of the bleeding disorder determines

the need for systemic prophylactic coverage in con-

junction with the local hemostatic measures (23). The

hemostatic deficiency in these patients can be cor-

rected by systemic and local measures (22). Thus,

coverage should be determined after consultation

with a hematologist. Inherited platelet disorders,

leading to bleeding or increased risk for bleeding, are

managed systemically with platelet transfusions (30).

Patients with moderate and severe thrombocytope-

nia, in which the platelet counts range from 50,000 to

100,000/ll and from 25,000 to 50,000/ll, respectively,

are candidates for extensive and prolonged bleeding

and definitely require platelet transfusion (30).

However, minor surgery, involving soft tissues, can

be performed with platelet counts as low as 30,000/ll

(30). Moreover, inherited coagulopathies are man-

aged systemically with replacement of coagulation

factors (9). Intravenous infusion of deficient, or

missing, coagulation factor starts 1 hour before the

procedure in order to achieve a level that is 30%

above the normal plasma concentration of this par-

ticular factor (22). The level has to be higher and to

reach 50% of the normal amount when regional

block anesthesia is administered (22). Proper treat-

ment planning addresses the half life of coagulation

factors, and treatment sessions are programmed

accordingly. For instance, factor VIII has a half life of

10–12 hours, and prophylactic coverage with factor

VIII is sufficient for dental treatment performed in

only one appointment (24, 25, 32, 44). In mild and

moderate inherited coagulopathies, desmopressin or

1-desamino-8-D arginine vasopressin can be useful.

Desmopressin induces the release of factor VIII/von

219

Bleeding disorders and periodontology

Willebrand Factor from platelets and endothelial

cells. Prior testing is required to determine the degree

of response to 1-desamino-8-D arginine vasopressin

(13, 21, 44, 51).

Management of patients with acquired bleeding

disorders is focused mainly on local hemostatic

measures that apply also to inherited bleeding dis-

orders. Professional cleaning, and scaling and root

planing, can be safely performed with the use of local

antifibrinolytic mouthwash, such as tranexamic acid

or epsilon aminocaproic acid (34). Intra-operative

local measures for periodontal surgical procedures

are very effective and control the bleeding tendency

in these patients. The type of periodontal surgical

procedure and potential for bleeding are important

aspects that must be taken into consideration. Re-

gional block anesthesia must be avoided. Local

infiltration anesthesia with the use of vasoconstric-

tive agent is desirable. Lidocaine 2% with 1:100,000

epinephrine is adequate. Articaine 4% with 1:100,000

epinephrine provides sufficient anesthesia for surgery

in the mandible. Another way to prevent excessive

bleeding is the meticulous handling of soft tissues.

Creating a conservative flap design and minimizing

flap elevation are key points. For surgical extractions,

tooth sectioning is helpful for preserving bone and

minimizing the involvement of anatomic spaces

around the surgical site. Mandibular molars should

be approached with a buccal flap and no reflection of

a lingual flap. To prevent secondary infection and

postoperative bleeding, there should be thorough

curettage of the extraction sockets and removal of all

granulation tissue. Extraction sockets of periodon-

tally involved teeth appear to have more potential for

bleeding after a procedure because of the increased

local infection in the area. In periodontal surgery,

primary closure of the flap is accomplished with

nonresorbable or resorbable sutures. Application of

pressure for 10 minutes with moistened gauze on the

flap has been suggested (59).

There are a number of commercially available local

hemostatic agents that enhance clot stabilization

(36). These include: absorbable gelatin (5, 21);

absorbable collagen (36); microfibrillar collagen (36)

and collagen dressings (36); oxidized regenerated

cellulose (26), thrombin (36), tranexamic acid (11, 12,

62) and epsilon-aminocaproic acid (45); fibrin glue

(6, 12, 17, 18, 26, 63); and platelet-rich plasma (64).

Collagen, gelatin and cellulose products provide the

scaffold for platelets to adhere to one another and

form the platelet plug. Thrombin converts fibrinogen

to fibrin and this contributes to the formation of the

fibrin clot. Tranexamic acid, along with epsilon

aminocaproic acid, inhibits plasminogen action and

reduces the fibrinolytic activity of the early formed

hemostatic clot. Fibrin glue consists of thrombin,

fibrinogen, fibronectin and aprotinin. Fibronectin

acts as a binding protein for the blood clot, and ap-

rotinin delays the degradation of the hemostatic clot.

Platelet-rich plasma contains growth factors released

by the platelets that accelerate the healing process

and thus enhance hemostasis.

Dental extractions and associated bleeding are

effectively managed with the insertion of a sponge

into the site (5). The sponge can be presoaked with an

antifibrinolytic agent, such as tranexamic acid or

epsilon aminocaproic acid. An absorbable gelatin

sponge should only be used in conjunction with

thrombin for this purpose (36). Fabrication of a sur-

gical splint for additional pressure and protection of

the site is recommended (2, 63). Another material

that has been used in the past to seal the extraction

site is cyanoacrylate (3).

At the end of surgery, patients susceptible to bleed-

ing are instructed to bite on a moistened gauze, or

gauze soaked with the hemostatic agent, for 30 min-

utes. After 30 minutes, the gauze is removed and the

surgical area is observed for oozing. If bleeding occurs,

additional measures are initiated. The surgical area is

re-entered and the bleeding source is identified. Elec-

trocautery and laser are used to control bleeding in the

soft tissues. When oozing arises from hard tissues,

bone burnishing and bone wax are the treatments of

choice. Once the bleeding is under control, the patient

may leave the site, but not without biting on a gauze

moistened with saline, a teabag or gauze soaked in

tranexamic acid (59).

Postoperative measures

Postoperative management is crucial for preventing

bleeding. General recommendations emphasize the

importance of good care of the surgical area. Rinsing is

prohibited on the day of surgery and the healing site

must be left undisturbed. Specific attention should be

given to tongue movements interfering with healing

and food intake. Liquids and a high-protein diet are

strongly recommended. The use of antifibrinolytic

mouthwash is highly recommended the day after

periodontal treatment. The regimen may comprise

rinsing with 10 ml of 4.8–5% tranexamic acid solution,

four times a day, for 2 minutes (22). The rinsing can be

carried out over a period of 2–5 days and may be

extended up to 8 days (22). The dental professional

should exercise caution in prescribing antibiotics and

pain medications. Antibiotics, such as penicillin,

220

Vassilopoulos & Palcanis

erythromycin, tetracycline, metronidazole, cephalo-

sporins, ampicillin and amoxicillin + clavulanic acid,

potentiate the coumarin action (31, 37, 59). Acetami-

nophen can also interact with coumarin and its use

must be limited to fewer than six tablets per week (59).

Clindamycin should be the antibiotic of choice in these

patients, and a lower dose of acetaminophen for a

short period of time is the regimen recommended for

postoperative pain control (59). When other medica-

tions are administered that affect coumarin bioavail-

ability or metabolism, supplemental international

normalized ratio tests are performed to evaluate the

anticoagulation effect (37).

Current concepts and newapproaches

Current concepts emphasize that the management of

patients with bleeding disorders can be carried out

safely in a dental office. Specific criteria must be met.

Dental professionals must be aware of the possible

development of bleeding complications and, as such,

management protocols should be implemented.

Communication and close co-operation with the

medical care professional and, particularly, with the

hematologist, is essential. The dental care provider

should give a detailed description of the dental pro-

cedure in order for the medical care professional to

obtain a good understanding of the planned proce-

dures and provide proper medical advice (67).

Minor and moderate invasive procedures can be

safely performed, even with an international nor-

malized ratio of 3.5, assuming that local hemostatic

measures are implemented (4). Low-molecular-

weight heparin may be viewed as a less expensive and

easier alternative for managing patients on antico-

agulation therapy who require alteration of the anti-

coagulation regimen (33). Antifibrinolytic mouthwa-

shes after scaling and root planing, localized pressure

applied to surgical flaps, and a collagen sponge

placed into extraction sockets, can be the sole treat-

ment in single coagulopathies (37). Taking a detailed

medical history, following the principles of hemos-

tasis and exercising rational clinical judgment, con-

tribute to the effective dental treatment of patients

with bleeding disorders.

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